Magnetic Resonance Spectroscopy (MRS) is an analytical method that can be used to identify and quantify certain metabolites in samples or areas of interest in the body. While relying on similar principles and using similar equipment, MRS differs from conventional Magnetic Resonance Imaging (MRI) in that the obtained spectra provide physiological and biochemical information about the sample, instead of anatomy and positional information used to form an image. By exploiting the magnetic properties of certain nuclei, MRS can provide detailed information about the structure, dynamics, reaction state, and chemical environment of the molecules in which they are contained. Similar to MRI, MRS is typically performed by placing the subject or object at or near the isocenter of a strong, uniform magnetic field, B0, known as the main magnetic field. The main magnetic field causes the nuclei (spins) in the matter comprising the subject or object to possess a magnetic moment. The spins form a magnetization that precesses around the magnetic field direction at a rate proportional to the magnetic field strength.
If the magnetization is perturbed by a small radio-frequency (RF) magnetic field, known as B1 magnetic field, the spins may emit RF radiation at a characteristic frequency. By applying the B1 magnetic field as one or more timed pulses and/or sequences of pulses with delay periods between them, the emitted RF radiation can be detected and analyzed to identify and quantify chemical compounds within an object and infer information about metabolic activity. Various techniques utilizing specific sequences of RF pulses with specific timing, frequencies, and intensities have been developed, providing new advances, as well as introducing new challenges.
MRS experiments can gather data in one-dimensional (1D MRS) or two-dimensional frequency or spectral space (2D MRS). Spectra obtained in 1D MRS relate to the chemical shift properties of the nuclei in the sample. More than 20 metabolites have been reported in the 1H-MRS spectra of the human brain (26, 27). 1D 1H-MRS on clinical MR scanners is hampered primarily by the difficulty in resolving dozens of peaks over a small spectral range of about 4 ppm. One solution is 2D MRS (28, 29), which increases the detectability of overlapping metabolites by spreading the spectrum into a second dimension. 2D MRS provides information on the structure of molecules and helps reliable assignment, quantification, and identification of metabolites (1). 2D localized chemical shift correlated spectroscopy (L-COSY) (10, 30-31) and 2D J-resolved spectroscopy (J-PRESS) (31, 32) are the most popular 2D MRS methods, though there are many derivations. 2D J-resolved spectroscopy can be used to analyze molecules for which their 1D MRS spectra contain overlapping resonance peaks (multiplets) due to J-coupling. J-coupling arises from the interaction of different spin states through the chemical bonds of a molecule and can provide insight into the connectivity of nuclei in a molecule. The 2D J-resolved spectrum vertically displaces the multiplet from each nucleus by a different amount. Each peak in the 2D J-resolved spectrum will have the same horizontal coordinate that it has in a non-decoupled 1D spectrum, but its vertical coordinate will be the J-coupling constants of the single peak that the nucleus has in a decoupled 1D spectrum.
Compared to J-resolved spectroscopy, COSY allows determination of the connectivity of a molecule by examining which spins are coupled. In turn, COSY yields better dispersion and more separation of J-cross peaks, allowing for better spectral quantification, despite requiring a larger spectral window to sample during the evolution period. Therefore maintaining the intensity of cross peaks is important for accurate and reliable quantification of COSY spectra.
MRS may benefit more from higher main magnetic field strengths than conventional MRI. The high-field magnets improve the sensitivity and specificity of the obtained spectral information by providing higher signal-to-noise ratio (SNR) and increased chemical shift dispersion (2, 3). The improved SNR also allows for shorter acquisition times or smaller detection volumes (1-3). The increased chemical shift dispersion improves the resolution of spectral information (1, 2). Despite these benefits, higher field strengths can cause shorter apparent transverse relaxation time (T2*) (4-6), longer longitudinal relaxation time (T1) (5), increased main static field (B0) and RF field (B1) inhomogeneity, and increased chemical shift displacement error (CSDE) (3). Further, the separation (or dispersion) of resonance peaks in MRS spectra is magnetic field dependent and the increased chemical shift dispersion sets higher demand on the bandwidth (BW) of RF pulses that are used for the localization for MRS. CSDE is proportional to the main static magnetic field (B0) and reversely proportional to the BW of slice-selective RF pulses (2, 7-9). In addition, the available RF power is usually more limited relative to the increased field strengths (2).
In 2D J-resolved spectroscopy, the limited BWs of RF pulses not only cause CSDEs but also lead to spatially dependent evolution of J-coupling (11), which results in additional J-refocused artifactual peaks (11-14). In J-PRESS; for a pair of coupled spins with a large chemical shift difference; one of the coupled spin pair may not undergo the 180° refocusing pulses due to the finite BW of the RF pulses in the voxel selected for its J-coupled partner. Therefore part of J-coupling will be refocused instead of evolving during the echo time (TE), which leads to additional so-called “J-refocused peaks” and at the same time attenuates the intensities of intended J-resolved peaks in a J-PRESS spectrum.
Unfortunately, a similar issue exists in L-COSY The basic COSY sequence is composed of two 90° RF pulses. The second 90° pulse mixes the spin states and transfers magnetization between coupled spins, which results in cross-peaks. In conventional 2D L-COSY, the sequence also includes one slice-selective 180° RF pulse (10), which will contribute to a larger CSDE than a slice-selective 90° RF pulse. The limited BW of the RF pulses for slice selection not only causes CSDE, but also leads to spatially dependent evolution of J-coupling (11), which results in additional J-refocused artifactual peaks in 2D J-resolved spectroscopy (11-14). Similarly in L-COSY, when the BWs of RF pulses are limited, one of the coupled spin pair may not undergo the second 90° pulse in the voxel selected for its J-coupled partner. As a result, magnetization transfer between coupled spins will not occur in part of the voxel, which leads to spatially dependent magnetization transfer and results in reduced cross peak intensity in L-COSY.
Accordingly, application of a second 90° RF pulse with limited BW will result in attenuated cross-peaks in L-COSY spectra. As cross peaks contain important information of the metabolites with coupled spin systems, compromised cross peaks will impair the quantification of L-COSY spectra. However, as will be described in full herein, this effect can be significantly suppressed when the second 90° RF pulse is not slice-selective, which can be better achieved by using an alternative semi-localization by adiabatic selective refocusing (semi-LASER) method for volume localization.
Adiabatic RF pulses, which have been applied for localization in MRS, can be used to address some of the issues related to CSDE (3, 7, 15-18, 33-38). Adiabatic pulses offer large BWs and produce a uniform flip angle despite variation in B1, provided that the B1 field strength is above a certain threshold. However, in contrast to conventional RF pulses, which can rotate magnetization around an axis in the rotating frame, a single adiabatic pulse cannot generate plane rotation (9, 16). If a pair of adiabatic refocusing pulses are used, the second adiabatic refocusing pulse can compensate or cancel the phase dispersion generated by the first adiabatic refocusing pulse. Therefore, a pair of adiabatic refocusing pulses is usually applied to define a slice. A single-shot spin-echo based sequence called LASER, which stands for “localization by adiabatic selective refocusing,” has been used for 1D MRS (16). LASER uses a non-slice-selective excitation pulse followed by three pairs of adiabatic full-passage (AFP) pulses for signal refocusing as well as selection of three orthogonal planes in space.
Recently, adiabatic localization was incorporated into basic COSY sequences. In one example, called “LASER-COSY,” which uses a non-slice-selective excitation pulse followed by three pairs of AFP pulses, was used for signal refocusing as well as volume selection (1, 18, 19). In another example sequence, called “sLASER-last-COSY,” which uses two pairs of AFP pulses and the second 90° RF pulse for volume localization (8). However, as will be discussed herein, the limited bandwidth of the slice-selective second 90° RF pulse used in sLASER-last-COSY induces spatially dependent magnetization transfer that results in attenuated cross-peaks and lower ratios of cross peak volumes to diagonal peak volumes. Further, LASER-COSY has a few disadvantages including significantly longer TE and higher specific absorption rate (SAR). Therefore, a need remains in the art for an improved 2D MRS technique that facilitates more reliable and accurate quantification of metabolites with coupled spin systems at 3 T and higher field strengths.